There is an urgent need for more effective medications for major depressive disorder (MDD) treatment, as less than 50% of depressed patients achieve full remission and many are not responsive, with currently available antidepressants. It is known that prolonged stressful events are an important cause of MDD. However, there is an intriguing difference in individual responses to stress: most people experiencing stressful events maintain normal psychological functioning (resilience to stress), whereas others develop depression (susceptibility to stress). Many psychosocial skills have been successfully used in our daily life to promote stress resiliency. Recent studies have begun to reveal the neurobiological basis for these psychosocial resilient factors, and show that positive emotions and mutual cooperation are linked to the function of the mesolimbic reward neural circuit. Consistent with this idea, we previously found that the activity of ventral tegmental area (VTA) dopamine (DA) neurons in the same reward circuit is a key determinant of susceptibility vs. resilience to social defeat stress. The firing rate of these neurons was significantly increased by chronic defeat in susceptible but not resilient mice. Furthermore, experimentally induced decreased firing promoted resilience, while increased firing promoted susceptibility. Surprisingly, at the molecular level, chronic defeat regulated more genes in resilient mice than in the susceptible subgroup, and induced dramatic upregulation of several K+ channels only in resilient mice, which may drive the higher firing back to normal levels. These findings strongly support the notion that a resilience phenotype is not simply a passive absence of stress-induced pathophysiology, but a promotable and active brain function by which animals successfully cope with stressful conditions via activation of more genes. In the current project, we ask: (1) whether the physiologically important firing patterns of VTA DA neurons encode the signal of stress vulnerability and play a role in active coping or deleterious behaviors;(2) whether we can find potential drug targets by understanding the molecular (ion channel and receptor) mechanisms of susceptibility and active resilience. Accordingly, we propose to use advanced optogenetic techniques to directly link specific firing patterns to stress susceptibility and resilience in freely-moving animals. We will also intensively explore the channel and receptor basis of defeat-induced changes in the firing properties of VTA DA neurons and particularly investigate the ionic mechanisms of active resiliency. Moreover, the roles of these new ionic and receptor mechanisms in mediating standard antidepressant action will be systematically investigated. These proposed molecular and cellular studies will provide very useful and highly novel information, both for improving our knowledge of depression and for identifying new drug targets to develop more effective treatments for depression. Such treatments would be based on imitating active coping mechanisms of naturally occurring resilience and therefore might be likely to be more effective and less prone to side effects. PUBLIC HEALTH RELEVANCE: Chronic stress can play a key role in the development of major depressive disorder. An important question is why some people are resilient to stress, while others are not resilient. Recently, we have segregated resilient and susceptible mice in an animal model of depression, and propose to explore how resilient mice successfully cope with stressful conditions and avoid developing stress-induced depression-like behaviors. These studies will greatly improve our understanding of resilience and susceptibility, and provide useful drug targets to develop new treatments for depression. We expect that our findings will be highly relevant to the mission of the NIH, particularly of the NIMH.